Epithelial Sodium Channel (ENaC) as a Novel Mechanism for Hypertension and Volume Expansion in Type 2 Diabetes

May 9, 2018 updated by: University of New Mexico

ENaC as a Novel Mechanism for Hypertension and Volume Expansion in Type 2 Diabetes

The purpose of this study is to determine with the administration of amiloride, observe an enhanced natriuresis, reduction in blood pressure and weight compared to the administration of hydrochlorothiazide in Type 2 Diabetics.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Detailed Description

Renal sodium retention and extracellular fluid volume expansion are hallmarks of nephrotic syndrome. There is abundant evidence that this occurs even in the absence of activation of hormones that are known to activate renal Na transporters. Proteinuria not only reflects glomerular damage, but also functions as a risk factor for cardiovascular disease, stroke, end stage renal disease and is associated with extracellular volume expansion and high BP.

In the natural course of Type II diabetes, microalbuminuria and elevations in blood pressure are thought to occur at around the same time. Blood pressure in microalbuminuric diabetics is more sensitive to dietary salt intake than in normoalbuminuric patients despite both groups having similar aldosterone and plasma renin activity levels. Proteolytic processing of ENaC subunits might provide the primary defect in renal sodium handling in these microalbuminuric individuals. However, proteinuria is not consistently identified as a risk factor for incipient elevation in blood pressure and in some studies elevated blood pressure predicts the advent of microalbuminuria.

Analyses of normotensive normoalbuminuric subjects in previous studies have found that higher urinary albumin levels in the normal range predicted incident hypertension. A similar finding was seen in a non-diabetic cohort. These studies suggest that these disparate results may be related to the cut off that defined microalbuminuria. Another possible explanation is that an ENaC activator, like plasmin, contributes to the generation of incident hypertension in some individuals. Levels of albuminuria may not necessarily be reflective of ENaC activator levels and may vary from individual to individual. Perhaps urinary plasmin and plasminogen provides a more robust biomarker for those individuals who may develop hypertension.

Recent evidence suggests that in some individuals with glomerular damage, proteases not normally found in urine enter the urinary space and aberrantly cleave ENaC. In this setting, filtered plasminogen (inactive precursor) is converted to plasmin (active protease) by urokinase that is expressed in tubular epithelial lumen. The proteolytic activation of ENaC would generate a primary defect in renal sodium handling, a mechanism that may be a particularly important factor leading to increases in extracellular fluid volume and BP that accompany nephrotic syndrome.

While previous studies have examined the role of amiloride in low-renin hypertension, and as an additional agent the conventional treatment of hypertension, no human trials have tested whether ENaC inhibitors impact blood pressure and volume status in the setting of proteinuria. Over a ten year period, millions of diabetics, 5.3% of Type II diabetics and 28% of Type I diabetics develop macroscopic proteinuria.

Study Type

Interventional

Enrollment (Actual)

9

Phase

  • Early Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • New Mexico
      • Albuquerque, New Mexico, United States, 87131
        • University of New Mexico Hospital; Clinical & Translational Science Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 80 years (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

  • Inclusion Criteria:

    1. Age 18 to 80 yrs at randomization
    2. History of Type 2 Diabetes
    3. Presence of systolic hypertension or pre-hypertension (average systolic blood pressure (SBP) ≥120 mmHg and <180 mmHg.)
    4. Urinary protein/creatinine ratio >300 mg/g creatinine at screening
    5. Hemoglobin A1C<8%
    6. Willing and able to give informed consent

  • Exclusion Criteria:

    1. Average SBP of ≥180 mmHg or diastolic blood pressure (DBP) of ≥110 mmHg
    2. Current symptomatic heart failure, history of New York Heart Association Class III or IV congestive heart failure, or left ventricular (LV) ejection fraction (by any method) <25%; these patients may be harmed with withdrawal of diuretics
    3. Serum potassium level <3.5 or >5.0 at screening
    4. History of hyperkalemia in the last two years (serum K>5.5)
    5. Contraindication to use of hydrochlorothiazide or amiloride
    6. Unstable angina pectoris or acute myocardial infarction (MI) in last 3 months
    7. Known secondary causes of hypertension (HTN) (screening for these conditions will not be required)
    8. Estimated glomerular filtration rate (GFR) <60 mL/min/1.73m², as determined by validated estimating equations
    9. On or expected to be on immunosuppressive therapy
    10. Any history of solid organ transplantation
    11. Significant dementia
    12. Other factors likely to limit adherence during trial (eg. alcohol or substance abuse, plan to move in next year, history of non-adherence to medications, appointments and medical care, reluctance of close family members to participate in trial, lack of support from primary healthcare provider)
    13. Participation in another investigational trial within 4 weeks of the screening visit
    14. Arm Circumference too large or too small to allow accurate blood pressure measurement
    15. Pregnancy or currently trying to become pregnant (although this is unlikely because of age limit
    16. Incarceration

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: HEALTH_SERVICES_RESEARCH
  • Allocation: RANDOMIZED
  • Interventional Model: CROSSOVER
  • Masking: DOUBLE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: Amiloride 10 mg, 20 mg, and diet
Amiloride 10 mg for 14 days and diet. Then dose titrated up at day 14 to 20 mg, and diet.
Drug: Amiloride

Amiloride 10 mg taken every day for two weeks, along with adherence to specified diet.

On day 14 titrate dose up to Amiloride 20 mg, take every day for two weeks after completion of two week intake of Amiloride 10 mg, along with adherence to specified diet.

Other Names:
  • Midamor
ACTIVE_COMPARATOR: HCTZ 12.5 mg, 25 mg and diet
HCTZ 12.5 mg for 14 days and diet. Then dose titrated up at day 14 to 25 mg, and diet
Drug: HCTZ

HCTZ 12.5 mg taken every day for two weeks, along with adherence to specified diet.

On day 14 titrate dose up to HCTZ 25 mg taken every day for two weeks after completion of two week intake of HCTZ 12.5 mg, along with adherence to specified diet

Other Names:
  • Microzide
  • HydroDIURIL
  • Aquazide H
  • Hydrochlorthiazide

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Blood Pressure
Time Frame: one month
Change in clinic systolic BP. This BP measure will be the average of three serial BP measurements taken one minute apart after 5 minutes of sitting quietly.
one month

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Hypertension
Time Frame: one month
To demonstrate effect size on relevant hypertension outcomes such as volume status and urinary sodium excretion. Also assess the fractional excretion of sodium (FENa) and chloride (FECI). Endpoint will be the 24 hour urine excretion.
one month

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of New Mexico

Collaborators

University of Pittsburgh
Dialysis Clinic, Inc.

Investigators

  • Principal Investigator: Mark L Unruh, MD MSc, University of New Mexico

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

March 1, 2013

Primary Completion (ACTUAL)

December 1, 2014

Study Completion (ACTUAL)

December 1, 2014

Study Registration Dates

First Submitted

March 1, 2013

First Submitted That Met QC Criteria

March 1, 2013

First Posted (ESTIMATE)

March 5, 2013

Study Record Updates

Last Update Posted (ACTUAL)

May 11, 2018

Last Update Submitted That Met QC Criteria

May 9, 2018

Last Verified

May 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 13-017 (Dana-Farber Cancer Institute)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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